Targeted radiotherapeutics utilize a molecular vehicle to selectively deliver radionuclides to malignant cell populations, with the most promising current approach being the use of radiolabeled monoclonal antibodies (MAbs). Our own studies in newly diagnosed and recurrent glioma patients have demonstrated that significant prolongation in median survival can be achieved with direct injection of 131I-labeled anti-tenascin 81 C6 MAb into surgically created resection cavities. Although encouraging results have been obtained, significant improvements in labeled MAb therapy will be required before radioimmunotherapy has a major impact on the clinical management of CNS tumor patients. Iodine-131 was utilized as the label because its low energy f3-particles are well matched to treating relatively small tumors; however, its 81%-abundant, 364-keV gamma-ray is problematic because it can increase radiation dose to normal organs, particularly the brain, prolongs patient confinement, and is not ideal for imaging. This research proposal is directed at developing the potential of 177Lu as a low-energy beta- emitting alternative to 131I for central nervous system tumor radioimmunotherapy. This 6.7-day half-life radionuclide is attractive because its gamma-emissions are considerably lower in energy and abundance than those of 131I. Its metallic character might be exploitable in designing better methods for labeling internalizing MAbs such as those reactive with the mutant epidermal growth factor receptor variant III (EGFRvIII). Our specific aims are: 1) to label anti-tenascin chimeric 81C6 MAb and F(ab')2 fragment with 177Lu and evaluate their potential as targeted radiotherapeutics for CNS tumors. The proposed studies include characterization of immunoreactivity and affinity; evaluation of tissue distribution and dosimetry in normal mice, and athymic rodents with subcutaneous, intracranial and neoplastic meningitis xenografts; and evaluation of therapeutic efficacy in these rodent xenograft models; 2) to label anti-EGFRvIII constructs with 177Lu and evaluate their potential as targeted radiotherapeutics for CNS tumors. Promising methods will be evaluated as outlined in Specific Aim 1; 3) to develop improved 177Lu labeling methodologies through the use of peptide linkers; and 4) to investigate the nature of the labeled catabolites generated in tumor cells in vitro and tumor and normal tissues in vivo and use these data as a guide for developing improved methods for labeling MAbs with 177Lu.